骨膜炎
心脏纤维化
血管紧张素II
纤维化
肌钙蛋白
肌成纤维细胞
基因敲除
转录因子
内科学
血清反应因子
医学
内分泌学
生物
癌症研究
细胞生物学
血压
基因
生物化学
细胞外基质
作者
Sikta Chattopadhyaya,Raghu S. Nagalingam,D Allison Ledingham,Michael P. Czubryt
出处
期刊:Physiology
[American Physiological Society]
日期:2023-05-01
卷期号:38 (S1)
标识
DOI:10.1152/physiol.2023.38.s1.5725178
摘要
Cardiac fibrosis involves the activation and conversion of fibroblasts to myofibroblasts in response to pathophysiological stresses, resulting in structural and functional remodeling of the heart leading to heart failure and death. Although it affects millions of people worldwide, currently no medications are available against cardiac fibrosis. Similar to the pro-fibrotic growth factor TGF-β, angiotensin II (AngII) contributes to cardiac fibrosis, however AngII inhibitors are not used against fibrosis despite growing evidence of efficacy. AngII induces the nuclear translocation of Myocardin Related Transcription Factor-A (MRTF-A) which acts with Serum Response Factor (SRF) to play a major role in the conversion of fibroblasts to myofibroblasts, similar to the transcription factor scleraxis. Scleraxis has been shown by our lab to induce fibrosis by transactivating various pro-fibrotic gene promoters. Here we investigated whether AngII works through an MRTF-A/SRF/scleraxis pathway to induce cardiac fibrosis. AngII delivery (1mg/kg/day for 28 days) through osmotic mini-pumps in C57Bl/6 mice significantly increased blood pressure (systolic, diastolic, and mean) and cardiac hypertrophy compared to saline control group. In the AngII group, cardiac fibrosis was observed with enhanced mRNA expression of pro-fibrotic genes, Col1a1, Col3a1, periostin, and EDA-fibronectin. Interestingly there was a significant increase in scleraxis as well, suggesting its involvement in AngII-mediated fibrosis. Our in vitro studies of rat cardiac fibroblasts treated with AngII showed a significant increase in scleraxis mRNA and protein expression, and scleraxis knockdown significantly attenuated AngII-induced collagen expression, confirming a requirement for scleraxis in the AngII-mediated fibrosis pathway. NIH3T3 cells transfected with MRTF-A and SRF together showed a high level of induction of scleraxis expression. Luciferase assays in both COS7 and NIH3T3 cells showed that MRTF-A and SRF act together to regulate scleraxis expression by binding to and transactivating the scleraxis promoter, indicating that AngII activates a MRTF-A/SRF/scleraxis pathway for inducing cardiac fibrosis, therefore targeting scleraxis may be an effective anti-fibrotic strategy. Canadian Institutes of Health Research Project Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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